Carrier for oromucosal administration of physiologically active substances

ABSTRACT

The invention relates to a carrier for oromucosal, especially sublingual administration of physiologically active substances, especially of medicinal drugs, which consists of at least one elastic layer ( 1 ) of polymer nanofibres workable according to the shape of the selected wall of mouth cavity to which it should be applied and in this elastic layer ( 1 ) of polymer nanofibres a drug and/or other physiologically active substance are deposited in a releasable manner.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional Application of U.S. patent applicationSer. No. 15/712,631, filed Sep. 22, 2017, currently pending, which is aContinuation Application of U.S. patent application Ser. No. 13/979,039,filed Aug. 16, 2013, now issued, which was a 35 U.S.C. § 371 NationalPhase conversion of PCT/CZ2011/000116, filed Dec. 12, 2011, which claimsbenefit of Czech Republic Application No. PV 2011-24, filed Jan. 17,2011, the disclosure of each of which is incorporated herein byreference. The PCT International Application was published in theEnglish language.

TECHNICAL FIELD

The invention relates to a carrier for oromucosal, especially sublingualadministration of physiologically active substances, especiallymedicinal drugs.

THE STATE OF THE ART

At present, the therapy of many diseases is connected withadministration of medicinal drugs. The most common form of drugadministration is oral administration by mouth, linked with swallowingof tablets or capsules, after which the drug passes through thegastrointestinal tract (GIT), where the drug is gradually released upon,especially in the stomach and in the intestine. Upon systemicadministration (in contrast to administration intended only for localaction in the GIT) the drug is, mostly only a certain portion of it,absorbed from the GIT into the blood or lymphatic system and transportedby it primarily into the liver. During this whole route the drug isbeing transformed in a certain manner. In many cases, its efficiency isthus reduced and with regard to this, the dose necessary to ensure thedesired action has to be increased. This may cause an increase inundesirable side effects of such a drug. There exists an important groupof drugs and/or physiologically active substances of which, for example,insulin can be mentioned. They are, when passing through thegastrointestinal tract and/or when being absorbed by its wall,especially by the stomach and intestinal wall, or during the subsequentfirst passage through the liver, completely or in a substantial extentinactivated or split into inactive metabolites. Therefore, there areother routes, for example parenteral routes of administration of suchdrugs (excluding the GIT). They include, for example, absorption from asublingual tablet through the mouth cavity mucosa, absorption frompatches or plasters into the skin, or intravenous administration byinjection or infusion.

For example, insulin is administered in a subcutaneous way, either usinga hypodermic needle, insulin pens or pumps. Sublingual administration ofthis substance seems to be impossible at present/as it is inactivated incontact with saliva and its absorption from badly definable absorptionsurface is in principle very variable.

Another group of physiologically active substances, where sublingualadministration seems to be reasonable, is represented by well absorbablesubstances with a rapid onset of action. These are the drugs belongingto the therapeutic groups treating, e.g. migraine pain, fast approachingpain attacks in cancer therapy, anxiety and panic states.

Other therapeutically interesting groups of substances, for which thesublingual administration seems to be possible and advantageous, arerepresented by the drugs for mitigation and therapy of Parkinson'sdisease, Alzheimer's disease, or schizophrenia.

The general advantages of sublingual administration of drugs includefast permeation of physiologically active substance through a relativelythin and permeable biological membrane, which does not exert its ownenzymatic activity and whose vasculature does not lead the absorbedsubstances directly to the liver. Therefore the sublingualadministration seems to be advantageous for administration of drugswhich have to be delivered into the blood circulation very quickly(drugs with rapid onset of action), which are not resistant to pH and toenzymes of GIT, and which undergo a high first-pass metabolism.

The problem of the present sublingual administration of drugs isespecially due to the fact that the surface of the sublingual mucosa inthe mouth cavity is under physiological conditions constantly washed bysaliva which is continuously swallowed. Also, activity of the tongueprevents a longer contact of the drug with the sublingual mucosa. Thesublingual tablets being used are thus formulated as very rapidlysoluble and serve for administration of the physiologically activesubstances which are capable to permeate through the sublingual membraneinto the vascular system very quickly before they are eitherdeteriorated by saliva and other substances present in the mouth cavity,or possibly swallowed with them.

From the professional literature are known non-fibrous membrane carriers(e.g. strips, films) and attempts to create drug carriers containing ananofibrous layer or layers produced by the use of electrospinning ofpolymer solutions or melts from a needle or a nozzle. A drug is appliedonto such a nanofibrous layer in the form of a liquid which is, e.g.,poured and dried, or a drug is layered in a solid state by extrusion. Adisadvantage of such a way of creating non-fibrous membranes, as well asthe nanofibrous layers, is their low air permeability and highfragility, which does not permit any realistic administration of theminto the sublingual space. During attempts to enable suchadministration, various platisticizers were used without significantpositive results. Another disadvantage consists in a difficultpre-defining of the quantity of a drug which sticks, with the use ofthese technologies of production, to the nanofibrous layer, andproblematic reproducibility of the final products resulting from it,because the nanofibrous layer is produced in small sizes and its dippinginto a solution of active ingredients or the administration of activesubstances using extrusion does not guarantee a repeatedly stable andreleasable quantity of the applied substance.

The goal of the invention is to create a carrier suitable for sublingualadministration of physiologically active substances, in particulardrugs, which would resolve the disadvantages of the state of the art andwould also enable further oromucosal administrations.

PRINCIPLE OF THE INVENTION

The goal of the invention has been achieved by a carrier for oromucosal,especially for sublingual administration of physiologically activesubstances, in particularly medicinal drugs. The essence is of theinvention is that the carrier comprises at least one elastic layer ofpolymer nanofibres being shapeable according to the shape of a selectedwall of the mouth cavity to which it should be applied, and in thiselastic layer of polymer nanofibres it contains a releasable drug and/orother physiologically active substance. The elasticity and shapeabilityof the layer of polymer nanofibres in the given context as a reservoirof the physiologically active substances, especially drugs, enables aperfect contact of the layer with the selected wall of the mouth cavity,thus enabling good penetration of the drug and/or other physiologicallyactive substance into this wall, or a possible transfer through it intothe vascular system and into the human or animal organisms. Workabilityand elasticity of the layer of nanofibres are achieved due to theproduction of a layer of nanofibres through needleless electrostaticspinning, in which simultaneously with a polymer also a drug and/orother physiologically active substance are being subjected to spinning,which are then deposited in a releasable manner in the layer ofnanofibres, and which can extend to the surface of the nanofibres or canbe on the surface of the nanofibres chemically or physically bound. Itis advantageous for an easy fixation on the selected wall of the mouthcavity if the layer of polymer nanofibres is on one of its sidesprovided with adhesive means, the adhesive means being preferably alayer of polymer nanofibres containing drugs and/or otherphysiologically active substances, or these means are represented by anelastic adhesive layer applied to the edges of the layer of polymernanofibres.

According to further embodiment of the invention, the layer of polymernanofibres containing a releasably deposited drug and/or otherphysiologically active substance is covered from all sides with anelastic and shapeable oromucosally non-adhesive covering layer. Thisembodiment has been designed to be inserted into the mouth cavitywithout fixation to some of the walls of the mouth cavity.

In one of its possible embodiments, the covering layer is permeable forsaliva and for substances contained in the mouth cavity and if a drugand/or other physiologically active substance is releasably deposited inthe layer of polymer nanofibres and is soluble by saliva and/or bysubstances contained in the mouth cavity, it is leached from the layerof nanofibres by saliva into the mouth cavity, where it acts at leastfor a period of its release.

For some administrations of the carrier it is at the same timeadvantageous if the covering layer is insoluble by saliva and bysubstances contained in the mouth: cavity, while it is permeable for adrug and/or other physiologically active substance releasably depositedin the layer of polymer nanofibres, and the drug and/or otherphysiologically active substance is released from the layer ofnanofibres in passive contact of the covering layer with the wall of themouth cavity and/or by pressure, e.g. during chewing. At this embodimentthe user must be in advance informed about for how long to hold thecarrier in his mouth so that the whole necessary dose of the drug and/orother physiologically active substance is released. For otheradministrations of the carrier, trie covering layer as well as the layerof polymer nanofibres are soluble by saliva and/or substances containedin the mouth cavity, while the period of time of their dissolution islonger than the time time of the release of the drug and/or otherphysiologically active substance from the layer of nanofibres, so thatafter the release of the drug and/or other physiologically activesubstance from the layer of nanofibres the layer of nanofibres as wellas the covering layer in the mouth starts to dissolve, which is thesignal for the user that the process is finished and the rest of thecarrier can be removed or swallowed.

Another important group of carriers according to the invention are thecarriers in which the layer of polymer nanofibres from the side whichshould be directed into the free space of the mouth cavity at theadministration of the carrier is covered by an elastic and workableoromucosally non-adhesive covering layer, while the other side of thelayer of polymer nanofibres remains free and by means of it the carriercan be fixed on the selected wall of the mouth cavity as describedabove.

A complete protection of the elastic layer of polymer nanofibres, inwhich a drug and/or other physiologically active substance is releasablydeposited, is achieved by a carrier whose principle consists in that thelayer of polymer nanofibres is covered from the side which should bedirected into the free space of the mouth cavity during theadministration of the carrier with an elastic and workable oromucosallynon-adhesive covering layer, and from the side designated to be incontact with some of the walls of the mouth cavity during administrationcovered with an elastic and workable protective layer, which ispermeable for the drug and/or other physiologically active substancesreleasably deposited in the layer of polymer nanofibres, by which itenables in contact with the respective wall of the mouth cavitypenetration of the drug and/or other physiologically active substanceinto this wall, as well as a possible transfer through it into thevascular system and into the human or animal organisms, while thecovering layer and the protective layer are connected on their edges.

To enable possible fixation of such a carrier to the selected wall ofthe mouth cavity, the protective layer is provided with at least oneadhesive means, which in the preferred embodiment consists of anadhesive layer applied to the edges of the protective layer. As a resultof this, the surface of the protective layer which is in contact withthe selected wall of the mouth cavity is reduced and the portion of thedrug and/or other physiologically active substance positioned behind theadhesive layer is not released from the layer of polymer nanofibres, oris being released slowly. Therefore this adhesive means can alsocomprise a portion of the drug and/or other physiologically activesubstance.

In the case required by the use of the above mentioned carrier, it canbe produced in such a way that the oromucosally non-adhesive coveringlayer and/or the protective layer overlap on the edges the layer ofpolymer nanofibres, in which the drug and/or other physiologicallyactive substance are releasably deposited and create a fixation rimaround it, surrounding at least partially its perimeter, while on theside designed for contact with some of the walls of the mouth cavity isthe fixation rim provided with an elastic adhesive layer, so that theadhesive layer does not reduce the effective surface of the layer ofpolymer nanofibres or the effective surface of the protective layercorresponding to this surface.

In an advantageous embodiment the fixation rim is formed of adhesivematerial, the whole protective layer designed for contact with some ofthe walls of the mouth cavity can be made of the adhesive material.

In an advantageous embodiment the protective layer can be made of alayer of nanofibres.

For some administrations of the carrier according to the invention, itis advantageous if the layer or layers of nanofibres containing the drugand/or other physiologically active substance and/or the covering layerand/or the protective layer is made of a material biodegradable by theaction of the medium in the mouth cavity, the time period ofbiodegradation being longer than the time period of the release of thedrug and/or other physiologically active substance. After releasing thedrug and/or other physiologically active substance from the layer ofpolymer nanofibres, there occurs biodegradation, which is the signal forthe user that the process of releasing has been accomplished and therest of the carrier can be removed or swallowed. In one of theadvantageous embodiments of the carrier according to the invention, thedrug and/or other physiologically active substance are a component ofnanofibres, which ensures elasticity and workability of the carrieraccording to the need to achieve a perfect transfer through the wall ofthe mouth cavity, for example through the sublingual mucosa, and makesit possible to deposit into the carrier only a very small quantity ofthe drug and/or other physiologically active substance, which isnevertheless sufficient for the required medical purpose. This decreasesthe toxic loading of the organism by the drug and in the highly priceddrugs also the costs of therapy.

For broader use of the carrier it is advantageous if it contains atleast two elastic and workable layers of polymer nanofibres and in eachof them a drug and/or other physiologically active substance aredeposited in a releasable manner.

At the same time in each layer of polymer nanofibres there a differentdrug and/or other physiologically active substance can be deposited andthe drugs and/or other physiologically active substances deposited inindividual layers can have different rates of release.

For the drugs and/or other physiologically active substances whichcannot be deposited into the layer of nanofibres during spinning, e.g.insulin, it is advantageous if these substances are impregnated into thelayer of polymer nanofibres placed between the covering and protectivelayers. In this embodiment the drug and/or other physiologically activesubstance are carried by the layer of polymer nanofibres, but they arenot bound in it.

DESCRIPTION OF THE DRAWINGS

FIG. 1 represents a view of the carrier according to the inventionformed only of a layer of nanofibers.

FIG. 2 shows the section of the carrier made of a layer of nanofibresand a covering layer placed on one side of the nanofibrous layer.

FIG. 2A depicts a section of the carrier according to FIG. 2 with afixation rim around the perimeter of the carrier.

FIG. 3 depicts a section of the carrier comprising a layer of nanofibresenclosed between the covering and protective layers from all sides.

FIG. 4 depicts a section of the carrier according to FIG. 3 with afixation rim made of a protective layer with adhesive properties.

FIG. 5 depicts long-term liberation profiles from nanofibres ofpolylactic acid with 5% of caffeine and with various layering.

FIG. 6A depicts layers of nanofibres from PCL polymers containingparacetamol in 5000× magnification.

FIG. 6B depicts layers of nanofibres from PLA polymers containingparacetamol in 5000× magnification.

FIG. 6C depicts layers of nanofibres from PVA polymers containingparacetamol in 5000× magnification.

FIG. 6D depicts layers of nanofibres from PAA polymers containingparacetamol in 5000× magnification.

FIG. 6E depicts layers of nanofibres from chitosan, crosslinked polymerscontaining paracetamol in 5000× magnification.

FIG. 6F depicts layers of nanofibres from gelatine, cross-linkedpolymers containing paracetamol in 5000× magnification.

FIG. 7A depicts layers of nanofibres from PVA with nabumetone, notoverlayered and not cross-linked in 5000× magnification.

FIG. 7B depicts layers of nanofibres from PVA with nabumetoneoverlayered with PAA, not cross-linked in 5000× magnification.

FIG. 8 depicts courses of liberation of nabumetone from polymer layers.

FIG. 9A depicts layers of nanofibres containing PVA with sumatriptane ina quantity of 5% for the dry mass of the polymer in 5000× magnification.

FIG. 9B depicts layers of nanofibres containing PVA with sumatriptane ina quantity of 5% for the dry mass overlayered with PVA in 5000×magnification.

FIG. 9C depicts layers of nanofibres containing PVA with sumatriptane ina quantity of 5% for the dry mass overlayered with chitosan in 5000×magnification.

FIG. 9D depicts layers of nanofibres containing PVA with sumatriptane ina quantity of 5% for the dry mass overlayered with PAA in 5000×magnification.

FIG. 10 graphically represents in vitro penetration of sumatriptane froma nanofibrous PVA carrier through the sublingual mucosa.

EXAMPLES OF EMBODIMENT

The carrier for oromucosal, in particular sublingual administration ofphysiologically active substances, especially drugs, comprises ananofibrous layer in which a drug and/or other physiologically activesubstance are releasably deposited, the drug and/or otherphysiologically active substance are either deposited directly innanofibres, of which it is a component and to whose surface it may rise,or they are situated in the space between the nanofibres and get alsostuck on their surface. The basic methods of how to implant the drugsinto the nanofibrous layer are coating, sinking or encapsulation bycoaxial and emulsion electrospinning.

Into the space between the nanofibres of the layer of polymer nanofibresa drug and/or other physiologically active substance can be deposited byapplying the drugs and/or other physiologically active substances on theproduced nanofibrous layer in the form of a solution or otherdispersion, which contains the drug and/or other physiologically activesubstance.

Onto a produced nanofibrous layer the drug and/or other physiologicallyactive substance can be applied by wetting the layer in a solution, orby spreading the dispersion, or by spraying. In the above-mentionedcases the basic problem is the unevenness of the quantity of the applieddrug and/or other physiologically active substance on the surface of thelayer of nanofibres, and further disadvantages rrientioned in the stateof the art section.

The evenness of distribution of a drug and/or other physiologicallyactive substance on the entire surface of the layer of polymernanofibres can be achieved by a process of sinking, i.e. dosing of thedrug and/or other physiologically active substance into a solution or amelt from which the nanofibrous layer is produced. The drug or otherphysiologically active substance are carried out from the solution ormelt together with the polymer and remain a component of the nanofibreor emerge to its surface, to which they remain fixed. The evenness ofdistribution of the drug and/or other physiologically active substancethus depends on the evenness in the distribution of polymer fibres inthe layer and on the evenness in the distribution of the diameters ofnanofibres in the layer. The required evenness can be achieved through along-term stable spinning process, which is at present represented byneedleless electrostatic spinning of a polymer matrix in an electricalfield created between the spinning electrode and the collectingelectrode, e.g. according to the European Patent EP 1673493, oraccording to the European Patent EP 2059630, or according to theEuropean Patent Registration Form EP 2173930.

The layer of polymer nanofibres containing a drug and/or otherphysiologically active substances prepared in this manner issubsequently divided into portions of specified size, weight and thusalso the content of a drug and/or other physiologically activesubstance. These portions of the layer of polymer nanofibres can becomethe carrier for oromucosal, especially for sublingual administration ofphysiologically active substances according to the inventionindependently, or they are a component of the carrier, which is at leastfrom one side covered by the protective layer. Due to the fact that theportions are made of a textile layer of polymer nanofibres, they areelastic and workable according to the shape of a given wall of the mouthcavity to which they should be applied.

In the embodiment according to FIG. 1 the carrier according to theinvention is made only of layer 1 of polymer nanofibres in which thereis a drug and/or other physiologically active substance depositedreleasably in nanofibres or on their surface. The layer of polymernanofibres represents a fibrous textile formation, whose basicproperties are elasticity and workability, and these properties are notaffected in any manner by the presence of the drug and/or otherphysiologically active substance. Elasticity and workability of thelayer of polymer nanofibres enable a perfect contact of the layer withthe given wall of the mouth cavity. It makes possible good penetrationof a drug and/or other physiologically active substance into thepertinent wall of the mouth cavity a, possible transfer through thiswall, e.g. through the sublingual mucosa, into the vascular system andinto the human or animal organisms. Elasticity and workability of thelayer of nanofibres results from the production of the nanofibrous layerusing needleless electrostatic spinning, during which also the drugand/or other physiologically active substance are subjected to spinningsimultaneously with the polymer, which is thus releasably deposited intothe layer of nanofibres and they can also extend to the surface ofnanofibres or can be bound on the surface of nanofibres eitherchemically or physically. The carrier can be used for oromucosal or forsublingual administration in the cases when it either does not matter,or when it requires leaching of the drug and/or other physiologicallyactive substance by saliva, and/or by the substances contained in themouth cavity, or in the cases when it contains drugs and/or otherphysiologically active substances, which are insoluble or very slowlysoluble by saliva and/or other substances contained in the mouth cavityand at the same time they are able to pass through the sublingual mucosaor through another wall of the mouth cavity to which they may beapplied. To secure the position on the respective Wall of the mouthcavity, layer 1 of nanofibres is provided on the side designed forcontact with given wall of the mouth cavity by at least one adhesivemeans, for example by elastic adhesive layer 11, designed to fix thecarrier oh the given wall of the mouth cavity. The adhesive layer 11 isin the represented embodiment in the corners of the portion made of ananofibrous layer forming the carrier, or it can be made along the edgesof layer 1 of nanofibres. The adhesive means can consist of the properlayer 1 of polymer nanofibres produced from a polymer suitable for thispurpose, e.g. a polysaccharide.

In the embodiment represented in FIG. 2, layer 1 of polymer nanofibrescontaining a drug and/or other physiologically active substances coveredfrom one side with oromucosally non-adhesive covering layer 2, while thefree side of layer 1 of nanofibres is designated for contact with thesublingual mucosa or some other wall of the mouth cavity and enablespenetration of the drug and/or other physiologically active substanceinto this wall, and possibly through it into the vascular system andinto the human or animal organisms. The covering layer 2 is usuallyimpermeable for saliva and substances contained in the mouth cavity andprevents leaching of physiologically active substances from the carrierinto the mouth cavity. That means that nearly all drugs and/or otherphysiologically active substances penetrate through the sublingualmucosa into the vascular system and into the human or animal organisms.That is why it is sufficient when in the portion of the layer ofnanofibres which is a component of the carrier only the required(necessary) quantity of a drug and/or other physiologically activesubstance are contained, which is sufficient to achieve the desiredmedical or physiological effect, without necessity to take into accountthe pertinent limits of bioavailability in other parts of the GIT.

In the production of layer of polymer nanofibres, covering layer 2 formsthe substrate layer on which nanofibres produced with the use ofelectrostatic spinning are deposited into the required layer. To createthe portions containing layer 1 of nanofibres and covering layer 2 andforming the carrier according to the invention, it is then sufficient tocut the produced layer of nanofibres together with the substrate layerin some of the routine manners, e.g. by means of a rotating knife. Tosecure the position on the respective wall of the mouth cavity, layer ofnanofibres is provided on the side designated for contact with theintended wall of the mouth cavity with adhesive layer 11. designed tofix the carrier to the specified wall of the mouth cavity. Adhesivelayer 11 is created on the edges of the portion of nanofibrous layer 1.In the advantageous embodiment of FIG. 2A, covering layer 2 overlapslayer 1 of nanofibres containing the drug and/or other physiologicallyactive substances and creates rim 21 around this layer. The adhesivemeans are deposited on the overlapping rim 21. Adhesive means arepreferably formed of adhesive layer 211, or the whole rim 21 can be madeof an adhesive material. In the not represented embodiment, the wholelayer of polymer nanofibres is produced from an adhesive material, inwhich the drug and/or other physiologically active substance aredeposited. Similarly, covering layer 2 can be made of an elastic andflexible layer of polymer nanofibres, which may exert adhesiveproperties.

In another not represented embodiment, covering layer 2 is permeable forsaliva and for substances contained in the mouth cavity, and the drugand/or other physiologically active substance releasably deposited inthe layer of polymer nanofibres are soluble by saliva and/or bysubstances contained in the mouth cavity. Once the carrier is insertedinto the mouth cavity, drug and/or other physiologically activesubstance are leached by the saliva from the layer of nanofibres intothe mouth cavity, in which it acts during its presence. This embodimentof the carrier is suitable especially for drugs and/or otherphysiologically active substances, for which it is necessary to remainin the mouth cavity for a certain period to show their activity. Suchsubstances can be e.g. antimicrobial agents, anti-inflammatory agents,analgetic agents designated to relieve pain including local anaesthesia,means for systematic hormonal therapy, means to influence immune system,agents for administration of enzymes, diagnostic agents, etc.

Covering layer 2 is according to one embodiment insoluble by saliva orby other substances contained in the mouth cavity; nevertheless it ispermeable for the drug and/or other physiologically active substanceswhich are releasably deposited in the layer of polymer nanofibres. Thedrug and/or other physiologically active substance is released from thelayer of nanofibres in passive contact of the covering layer with thewall of the mouth cavity and/or by pressure, e.g. during chewing.

In another embodiment of the carrier, covering layer 2 as well as layer1 of polymer nanofibres are soluble by saliva and/or by substancescontained in the mouth cavity. The period of time of the dissolution ofcovering layer 2 as well as of layer 1 of nanofibres is longer than thetime period of the release of the drug and/or another physiologicallyactive substance from layer 1 of nanofibres, so that after the releaseof the drug and/or another physiologically active substance from layer 1of nanofibres, the layer of nanofibres as well as the covering layer 2start to dissolve in the mouth, which is the signal for the user thatthe process of the release of the drug and/or another physiologicallyactive substance is accomplished, and the rest of the carrier can beremoved from the mouth or can be swallowed.

Another important group of carriers according to the invention are thecarriers in which the layer of polymer nanofibres is covered from theside which should be directed into a free space of the mouth cavityduring administration of the carrier by an elastic and workableoromucosally non-adhesive covering layer 2, while the other side oflayer 1 of polymer nanofibres remains free, and by means of it thecarrier can be fixed on the selected wall of the mouth cavity asdescribed above. Such a carrier represents one of the basic embodimentsof the carrier according to the invention.

FIG. 3 shows another variant of the carrier according to the invention.In this embodiment layer 1 of polymer nanofibres containing a drugand/or other physiologically active substances is covered from the sidewhich should be directed to a free space of the mouth cavity duringadministration of the carrier by the elastic and workable oromucosallynon-adhesive covering layer 2, possibly adhesive, and from the otherside by the protective layer 3, preferably adhesive, designated forcontact with the respective wall of the mouth cavity, and the coveringlayer 2 as well as the protective layer 3 are joined on edges, so thatthe layer 1 of nanofibres is enclosed between them from all sides.

In the production of layer 1 of polymer nanofibres, e.g. covering layer2 forms the substrate layer, on which the nanofibres produced byelectrostatic spinning are deposited into the required layer 1. In thefurther step, to the layer 1 of nanofibres the protective layer 3 isapplied, preferably an adhesive one, which can be made of another layerof nanofibres permeable for the drug and/or other physiologically activesubstances deposited in the nanofibres of the basic layer of nanofibres.The protective layer 3 can be also made of another suitable, adequatelyadhesive textile permeable for the drug and/or other physiologicallyactive substances deposited in rianofibres of the basic layer ofnanofibres. In this case the inner protective layer 3 is deposited onthe surface of the layer 2 of nanofibres outside the spinning space. Tocreate the portions 1 composed of the layer 1 of polymer nanofibres, thecovering layer 2 and the protective layer 3 and forming the carrieraccording to the invention, it is then sufficient to cut the producedlayer of nanofibres together with the covering layer 2 and theprotective layer 3 in some of the routine manners, e.g. by means of afusing rotating knife, in which by the action of heat and pressureduring cutting the edges of cut-out portions join together. Cutting canbe realized also by means of ultrasound or a laser.

A common technological arrangement for an expert is the variant in whichthe substrate textile, on which the layer of polymer nanofibres isdeposited during production, is made of protective layer 3 and on thelayer 1 of nanofibres the covering layer 2 is deposited.

To secure the position on the respective wall of the mouth cavity, onthe side serving for contact with the pertinent wall of the mouthcavity, the inner protective layer 3 is provided with an adhesive means,e.g. adhesive layer 31, designated to fix the carrier on the specifiedwall of the mouth cavity. The adhesive layer is produced on the edges ofthe layer 1 of nanofibres.

In the basic embodiment the carrier in the embodiment according to FIG.3 serves to release drugs and/or other physiologically active substancesdeposited in nanofibres of the layer 1 of polymer nanofibres through thespecified wall of the mouth cavity, usually through the sublingualmucosa, to which it was applied by its inner protective layer 3. Theinner protective adhesive layer 3 is permeable for drugs and/or otherphysiologically active substances and all drugs and/or otherphysiologically active substances penetrate the inner protective layer 3and the sublingual mucosa into the vascular system and into the humanand animal organisms in a 5000× magnification, while the externalcovering layer 2 is impermeable for saliva and other substances in themouth cavity and during the whole period of releasing it preventsleaching of the drug and/or other physiologically active substance fromthe carrier into the mouth cavity.

In another embodiment, covering layer 2 of the carrier is permeable forsaliva and for substances contained in the mouth cavity, and the drugand/or other physiologically active substances deposited releasably innanofibrous layer are at least partially soluble by saliva and/orsubstances contained in the mouth cavity, or at least some of them aresoluble. The inner protective layer 3 is at this embodiment providedwith at least one adhesive means, e.g. by peripheral adhesive layer 31,by means of which the carrier may be attached to the specified wall ofthe mouth cavity. In the case when in the inner space of carrier atleast two layers A of nanofibres are used, a different drug and/oranother physiologically active substance can be deposited in each ofthem.

To secure perfect fixation of the carrier in the mouth cavity, thecovering layer 2 as well as the protective layer 3 overlap the edges ofthe portion of layer 1 of polymer nanofibres, in which the drug and/orother physiologically active substance are releasably deposited, andform fixation rims 21 or 31 around it. On the side designated forcontact with some of the walls of the mouth cavity, fixation rims 21, 31are provided with flexible adhesive layers 211, 311. In the advantageousembodiment the fixation fell 21, 31. is created from an adhesivematerial, for example from polysaccharide.

In the embodiment according to FIG. 4, the adhesive material, e.g. apolysaccharide, forms the whole protective layer 3, from which alsofixation rim 31 is created, and at the same time for securing goodpermeability of the drug and/or other physiologically active substancewhich is being released from layer 1 of polymer nanofibres, protectivelayer 3 is made of a layer of nanofibres.

In another example of the embodiment, layer 1 or layers of polymernanofibres containing a drug and/or other physiologically activesubstance and/or the covering layer 2 and/or protective layer 3 are madeof a material biodegradable by the action of the medium in the mouthcavity, the period of time of biodegradation being longer than the timeperiod of releasing the drug and/or other physiologically activesubstance. After the drug and/or other physiologically active substanceis released from the layer of polymer nanofibres, biodegradation of thecarrier takes place, which is the signal for the user that process ofthe release of the drug and/or other physiologically active substance isaccomplished and the rest of the carrier can be removed or swallowed.

In another advantageous embodiment which further extends the sphere ofthe administration of the carrier according to the invention, thecarrier consists of at least two elastic and workable layers 1 ofpolymer nanofibres, and in each of them a drug and/or otherphysiologically active substance are releasably deposited. In each,layer 1 of polymer nanofibres a different drug and/or otherphysiologically active substance is deposited in a releasable manner.They may have identical or different releasing rates from respectivelayers 1 of polymer nanofibres.

For drugs and/or other physiologically active substances which cannot beincorporated into the layer of nanofibres during spinning, e.g. insulin,these substances are impregnated into the layer of polymer nanofibresarranged between the covering layer and the protective layer. In thisembodiment the drug and/or other physiologically active substance arecarried by the layer of polymer nanofibres, nevertheless they are notbound in it.

Below are shown model examples for the production of textiles withnanofibrous layers, which are elastic and workable and contain a drugand/or other physiologically active substances. These examples are shownas the model ones and are not intended to limit the invention to thesubstances mentioned in the examples, whether they; are polymers,solvents, physiologically active substances or the concrete methods ofproduction, etc.

Example 1

A Biodegradable Layer of Nanofibres with Caffeine Covered with aNonbiodegradable Layer

Polyurethane (PUR) was selected to serve as a non-biodegradable layerdue to its widely spread administration in medicine, andpolycaprolactone (PCL) was tested as a biodegradable layer.Polycaprolactone was subject to spinning as a 12% solution from AA:FA2:1, with an addition of caffeine (5% by weight for polymer), in 13% PURin DMF:toluene 2:1 still prior to spinning its conductivity wasincreased by means of tetraethylammoniumbromide (TEAB) to 30 pS.

PCL with caffeine on a 0.5 m line electrodes spinning (SE) 6-wirecollecting (CE) cylinder distance (mm) 180 SE length (mm) 250 CElength(mm) 500 speed SE/min 5 voltage SE (kV) 60 CE (kV) −5 PUR on a 0.5m line electrodes spinning (SE) 6-wire collecting (CE) cylinder distance(mm) 170 SE length (mm) 250 CE length (mm) 500 speed SE/min 5 voltage SE(kV) 60 CE (kV) −5 temperature 22° C., humidity 45%

Example 2

Totally Biodegradable Layers of Nanofibres with Incorporated Caffeine

For the production of totally biodegradable double layers, combinationsof polylactic acid and polycaprolactone were proposed, viz. PLA withcaffeine+PLA, PCL with caffeine+PCL, PLA with caffeine+PCL and PCL withcaffeine+PLA. The double layer PCL. with caffeine+PCL was prepared usingan NS LAB 500 device from the solution AA:FA 2:1 consisting of 12% ofpolymer, possibly also the model substance caffeine. All other layerswere produced on an EMW prototype 1600; PCL from the same solution asthat on the LAB and PLA from CHCl3:DCE:EtAc 61:29:10 as a 7% solution,with an addition of 1 g of TEAB to 100 g of solution. The layers withcaffeine contained always 5 weight percent of this model substance forpolymer dry mass.

Detailed conditions for spinning are shown in the following table.

PLA and PLA with caffeine, EMW 1600 prototype electrodes spinning (SE)wire (3x) collecting (CE) wire (3x) distance (mm) 180 SE length (mm)1000 CE length (mm) 1000 voltage SE (kV) 60 CE (kV) −20 temperature 22°C., humidity 29% PCL and PCL with caffeine, EMW 1600 prototypeelectrodes spinning (SE) wire (3x) collecting (CE) wire (3x) distance(mm) 180 SE length (mm) 1000 CE length (mm) 1000 voltage SE (kV) 60 CE(kV) −20 temperature 21° C., humidity 30%

PCL and PCL with caffeine on NS LAB 500 electrodes spinning (SE) 5-wirecollecting (CE) cylinder distance (mm) 170 SE length (mm) 200 CE length(mm) 500 speed SE/min 5 voltage SE (kV) 70 CE (kV) — temperature 22° C.,humidity 26%

Long-term liberation profiles from nanofibres of polylactic acid with 5%of caffeine and various layering are represented in FIG. 5.

Example 3

Nanofibrous Layers with Paracetamol

During the incorporation of paracetamol (N-acetyl-p-aminophenol) intonanofibres, the crushed commercially available preparation PARALEN® 500was added into the polymer solution before spinning. The preparation isvery well soluble in water, which makes its administration incombination with biopolymers spun mostly from aqueous solutions moreadvantageous. In solvent mixtures containing water, paracetamol producedideal solutions. Spinning of specified biopolymers was performed usingan NS LAB 500 device, spinning of PLA on an EMW prototype 1600.

FIG. 6 shows the produced layers, in the case of necessity alreadycross-linked. Verification of paracetamol content was done only fororientation purposes according to the surface weight, which in thesamples with paracetamol was naturally’ higher than in the clean layerswithout the drug. The following table gives a list of solutionssubjected to spinning, including the paracetamol content for dry mass,and simultaneously the conditions of individual processes.

The essay resulted in the production of very neat fibres having atransverse diameter of 80-600 nm, only in the case of gelatine thereoccurred some thickened fibres, in PCL besides the thickened fibres theballs of the polymer were also present.

12% PCL AA:FA 2:1 + 5% paracetamol for dry mass electrodes spinning (SE)5-wire collecting (CE) cylinder distance (mm) 180 SE length (mm) 200 CElength (mm) 500 speed SE/min 5 voltage SE (kV) 75 CE (kV) — temperature20.5° C., humidity 30% 11% (PVA + PEO) in H₂O + 5% paracetamol for drymass electrodes spinning (SE) cylinder collecting (CE) cylinder distance(mm) 125 SE length (mm) 200 CE length (mm) 500 speed SE/min 2.5 voltageSE (kV) 55 CE (kV) — temperature 22° C., humidity 29% Cross-linking 145°C., 15 min 2.25% chitosan AA:H₂O 2:1 + 10% paracetamol for dry masselectrodes spinning (SE) 5-wire collecting (CE) cylinder distance (mm)190-175 SE length (mm) 200 CE length (mm) 500 speed SE/min 3 voltage SE(kV) 80-82 CE (kV) — temperature 22° C., humidity 28% cross-linking 130°C., 10 min 7% PLA CHCl₃:DCE:EtAc 61:29:10 + 5% paracetamol for dry masselectrodes spinning (SE) wire (3x) collecting (CE) wire (3x) distance(mm) 180 SE length (mm) 1000 CE length (mm) 1000 speed SE/min — voltageSE (kV) 60 CE (kV) −20 temperature 21° C., humidity 33% 5% PAA in 0.1MNaCl + beta- cyclodextrin 20% + paracetamol 5% electrodes spinning (SE)cylinder collecting (CE) cylinder distance (mm) 180 SE length (mm) 200CE length (mm) 500 speed SE/min 2 voltage SE (kV) 35-40 CE (kV) —temperature 24.5° C., humidity 31-32% Cross-linking 145° C., 12 min 11%gelatine AA:H₂O 4:1 + 5% paracetamol for dry mass electrodes spinning(SE) cylinder collecting (CE) cylinder distance (mm) 150 SE length (mm)200 CE length (mm) 500 speed SE/min 2 voltage SE (kV) 70 CE (kV) —temperature 21° C., humidity 29% cross-linking: vapours of 25%glutaraldehyde, 1-2 h

Example 4

Nanofibrous Layers with Nabumetone

Nabumetone, (4-(6-methoxy-2-nafthyl)-2-butanon), belongs to the group ofnon-steroidal anti-inflammatory drugs (NSAID) and is used to cureinflammations and pains e.g. in arthritis. This derivative of1-naphthaleneacetic acid is very well soluble in water and can beincorporated with advantage into the polymers spun from aqueoussolutions. For experiments with nabumetone, an addition of this druginto polyvinyl alcohol and polyacrylic acid was proposed.

11% (PVA + PEO) in H₂O + 5% nabumetone for dry mass electrodes spinning(SE) cylinder collecting (CE) cylinder distance (mm) 130 SE length (mm)200 CE length (mm) 500 speed SE/min 2.5 voltage SE (kV) 60 CE (kV) —temperature 22° C., humidity 30% cross-linking 145° C., 15 min 2.25%chitosan AA:H₂O 2:1 overlayering electrodes spinning (SE) cylindercollecting (CE) cylinder distance (mm) 160 SE length (mm) 200 CE length(mm) 500 speed SE/min 3 voltage SE (kV) 82 CE (kV) — temperature 22° C.,humidity 29.5% 5% PAA in 0.1M NaCl + beta- cyclodextrin 20%,overlayering electrodes spinning (SE) cylinder collecting (CE) cylinderdistance (mm) 170 SE length (mm) 200 CE length (mm) 500 speed SE/min 3voltage SE (kV) 60-65 CE (kV) — cross-linking 20 min at 145° C.

Double layers were produced consisting of a biodegradable layer with adrug overlayered with a biodegradable polymer, i.e. PVA with nabumetoneoverlayered with pure PVA, chitosan or polyacrylic acid.

To both biopolymers always 5% of nabumetone for dry mass was added,already into the solution before spinning.

The spinning itself was performed on a NS LAB 500 device under theconditions shown in the table below. Due to the spinning of PVA as wellas PAA from aqueous solution, it was necessary to perform cross-linkingof the samples before dispatch.

FIGS. 7a, 7b show the pictures of samples before cross-linking.

The courses of liberation of nabumetone from polymer layers producedthrough electrostatic spinning of PVA, combination of PVA with chitosan(CHI) and combination of PVA with PAA are shown in FIG. 8.

Example 5

Nanofibrous Layers with Sumatriptane

Sumatriptane,(1-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-N-methyl-methanesulfonamide),belongs to the drugs with an antimigranious effect used to cure aheadache. Due to its good solubility in water this drug was selected tobe incorporated into biopolymers spun mostly from water.

Totally biodegradable double layers combining PVA, PAA and chitosan wereproduced. Namely the drug was incorporated into the fibres of polyvinylalcohol and subsequently overlayered with pure PVA, chitosan orpolyacrylic acid.

In the solution itself prior to spinning and after, pH, the decisiveparameter for the occurrence of sumatriptane in its ionised ornon-ionised form, was monitored. For the whole time the value of pHvaried in the range of 2-3, i.e. in a strong acidic range. All sampleswere cross-linked under the conditions of cross-linking of PVA (145° C.,20 min), though for chitosah a shorter period of time and a lowertemperature would be sufficient.

The following table submits a detailed survey of the conditions of theproduction process of layers and membranes. The photos of the producedcross-linked samples from an electron microscope in 5000× magnificationare shown in FIG. 9 and in vitro penetration of sumatriptane through thesublingual mucosa of nanofibrous PVA carrier is presented in FIG. 10.

11% (PVA + PEO) in H₂O + sumatriptane 5% for dry mass electrodesspinning (SE) cylinder collecting (CE) cylinder distance (mm) 130 SElength (mm) 200 CE length (mm) 500 speed SE/min 2.5 voltage SE (kV) 60CE (kV) — 2.25% chitosan AA:H₂O 2:1 overlayering electrodes spinning(SE) cylinder collecting (CE) cylinder distance (mm) 160 SE length (mm)200 CE length (mm) 500 speed SE/min 3 voltage SE (kV) 82 CE (kV) —temperature 22° C., humidity 29.5% 11% (PVA + PEO) in H₂O overlayeringelectrodes spinning (SE) cylinder collecting (CE) cylinder distance (mm)130 SE length (mm) 200 CE length (mm) 500 speed SE/min 2.5 voltage SE(kV) 60 CE (kV) — 5% PAA in 0.1M NaCl + beta- cyclodextrin 20%,overlayering electrodes spinning (SE) cylinder collecting (CE) cylinderdistance (mm) 170 SE length (mm) 200 CE length (mm) 500 speed SE/min 3voltage SE (kV) 60-65 CE (kV) — cross-linking 20 min at 145° C.

APPLICABILITY IN INDUSTRY

The carrier according to the invention has been designed for oromucosal,especially sublingual administration of physiologically activesubstances, especially of medicinal drugs. Sublingual administration ofdrugs and/or other physiologically active substances, when compared withoral administration, makes it possible to substantially reduce the totaldose of a drug and/or other physiologically active substanceadministered into the organism, which reduces toxicological loading ofthe organism, and in the case of expensive medicaments it also decreasesthe cost of therapy. In comparison with injection administration, theadministration is painless and in comparison with inhalationadministration it features higher reproducibility.

1. A method for preparing nanofibers by electrospinning, whichnanofibers comprise a mixture of polymers, including a polymer suitableas an adhesive to a wall of a mouth cavity and a drug and/or otherphysiologically active substance, the method comprising (i) dissolvingor suspending the polymer suitable as an adhesive to a wall of a mouthcavity in a solvent to obtain a solution; (ii) dissolving or suspendingthe drug or other physiologically active substance in the solution toobtain a mixture; and (iii) electrostatic spinning the mixture to obtaintwo or more layers of nanofibers; wherein the two or more layers ofnanofibers comprise a nanofiber layer characterized by at least aportion of the polymer suitable as an adhesive to a wall of a mouthcavity attached to a polymer layer comprising the drug or otherphysiologically active substance.
 2. The method of claim 1, furthercomprising dissolving or suspending a polymer suitable as a coveringlayer in a solvent to obtain a second solution; and electrostaticspinning the second solution to obtain the covering layer, wherein thetwo or more layers of nanofibers are positioned on the covering layerafter electrostatic spinning the mixture and electrostatic spinning thesecond solution.
 3. The method of claim 2, wherein the polymer suitableas a covering layer comprises polycaprolactone.
 4. The method of claim2, wherein the two or more layers of nanofibers comprise the drug orother physiologically active substance evenly distributed across the twoor more layers.
 5. A method of producing a carrier for oromucosaladministration of physiologically active substances to a subject,comprising: (i) dissolving or suspending a first polymer suitable forforming a physiologically acceptable nanofiber in a solvent to obtain asolution; (ii) dissolving or suspending a drug or other physiologicallyactive substance in the solution to obtain a mixture; (iii)electrostatic spinning the mixture to obtain a flexible layer ofnanofibers comprising the drug or other physiologically activesubstance; and (iv) dividing the flexible layer of nanofibres into aplurality of portions based on a predetermined specified size or apredetermined weight, wherein the flexible layer of nanofibers comprisesthe drug or other physiologically active substance evenly distributedacross the flexible layer.
 6. The method of claim 5, further comprisingdissolving or suspending a second polymer suitable as a covering layerin a solvent to obtain a second solution; and electrostatic spinning thesecond solution to obtain the covering layer, wherein the flexible layerof nanofibers is positioned on the covering layer after electrostaticspinning the mixture and electrostatic spinning the second solution. 7.The method of claim 6, further comprising: (i) dissolving or suspendinga third polymer suitable for forming a physiologically acceptablenanofiber in a third solvent to obtain a third solution; (ii) dissolvingor suspending a second drug or other physiologically active substance inthe third solution to obtain a third mixture; (iii) electrostaticspinning the third mixture to obtain a second flexible layer ofnanofibers comprising the second drug or other physiologically activesubstance.
 8. The method of claim 7, wherein the first polymer and thethird polymer comprise different polymers, wherein when subject toelectrostatic spinning, nanofibers comprising the first polymer andnanofibers comprising the third polymer each have a different rate ofrelease of the first drug or other physiologically active substance andthe second drug or other physiologically active substance in a mouthcavity of a subject.
 9. The method of claim 5, wherein the drug or otherphysiologically active substance comprises two or more different drugsor physiologically active substances.
 10. The method of claim 9, whereinthe method further comprises (i) dissolving or suspending a secondpolymer suitable for forming a physiologically acceptable nanofiber in asecond solvent to obtain a second solution; (ii) dissolving orsuspending a second drug or other physiologically active substance inthe second solution to obtain a second mixture; (iii) electrostaticspinning the second mixture to obtain a second flexible layer ofnanofibers comprising the second drug or other physiologically activesubstance, wherein the second flexible layer of nanofibers comprises thesecond drug or other physiologically active substance evenly distributedacross the second flexible layer.
 11. The method of claim 10, whereinthe second mixture is combined with the first mixture prior toelectrostatic spinning.
 12. The method of claim 5, wherein the flexiblelayer of nanofibers is composed of nanofibers having a transversediameter range between 80-600 nm.
 13. The method of claim 5, wherein theelectrostatic spinning comprises an electrical field created between aspinning electrode and a collecting electrode to produce the flexiblelayer of nanofibers comprising the drug or other physiologically activesubstance evenly distributed across the flexible layer.
 14. The methodof claim 5, wherein the process further comprises coating or sinking theflexible layer of nanofibers, or one of more of the plurality ofportions, in a solution comprising the drug and/or other physiologicallyactive substance.